Synthetic cephalosporins



United States Patent Oflice 3,391,141 Patented July 2, 1968 3,391,141SYNTHETIC CEPHALOSPORINS William Joseph Gottsteiu, Fayetteville, and AnnHallstrand Eachus, Syracuse, N.Y., assignors to Bristol- Myers Company,New York, N.Y., a corporation of Delaware No Drawing. Filed July 7,1966, Ser. No. 563,355 16 Claims. (Cl. 260-243) This invention relatesto new synthetic compounds of value as antibacterial agents, asnutritional supplements in animal feeds, as agents for the treatment ofmastitis in cattle, and as therapeutic agents in poultry and animals,including man, in the treatment of infectious diseases caused byGram-positive and Gram-negative bacteria and, more particularly, relatesto certain 7-[N,N-disubstituted-carbarnoyl (andthiocarbamoyl-)mercapto-acetamido]cephalosporanic acid and related saltsand derivatives.

Antibacterial agents in the past have proven highly effective in thetherapy of infections due to either Grampositive or Gram-negativebacteria but few are effective against both. It was the objective of thepresent invention to provide novel compounds effective against bothGrampositive and Gram-negative bacteria including the resistant strains.It was a further object of the present invention to providecephalosporins active against Grampositive and Gram-negative bacteriawhich are also efficiently absorbed upon parenteral or oraladministration to man and animals.

The objects of the present invention have been achieved by theprovision, according to the present invention, of the compounds of theformula wherein X is oxygen or sulfur, B is a secondary amino group; Ais hydrogen, hydroxyl, (lower)alkanoyloxy con taining 2-8 carbon atoms,e.g., acetoxy, propionoyloxy, butanoyloxy, pentanoyloxy, etc.benzoyloxy, a quaternary ammonium radical, e.g. pyridinium, quinolinium,picolinium, lutidinium, or, when taken together with M, a. m-onovalentcarbon-oxygen bond; and M is hydrogen, a pharmaceutically acceptablenontoxic cation, an anionic charge when A is the quaternary ammoniumradical, or, when taken together with A, a monovalent carbon-oxygenbond.

The term (lower)alkyl as used herein means both straight and branchedchain aliphatic hydrocarbon radicals having from 1 to 6 carbon atomssuch as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl,amyl, hexyl, etc. Similarly, where the term (lower) is used as part ofthe description of another group e.g. (lower) alkoxy, it refers to thealkyl portion of such group which is therefore as described above inconnection with (lower)alkyl and thus includes such radicals asmet'hoxy, ethoxy, isopropoxy, etc.

In addition to the secondary amino groups in which two bonds of thenitrogen atom form part of a nonaromati-c carbocyclic or herterocyclicring, the term secondary amino group includes, but is not limited to,groups of the formula in which each of A and 13 represents a radicalselected from the following list:

(1) Aliphatic radicals, for example:

Alkyl radicals, e.g.:

Methyl Ethyl Propyl (nand iso-) B'utyl (n-, sec-, iso', and tert-) A'myl(n-, sec-, iso-, and tert-) Hexyl radicals, e.g.: n-Hexyl Sec-hexyl2,2-dimethyl-3 butyl 2,2-dimethyl-4-butyl 2,3-dimet-hyl-2-butylZ-methyl-l-pentyl 2-methyl-2-pentyl 3-methyl-lpentyl 3-methyl-2-pentyl,etc. Heptyl radicals, e.g.:

n-Heptyl Sec-hepty-l 2,3-dirnethyl-3-pentyl 2,4-dimethyl-2-pentyl2,4-dimethyl-3-pentyl 2,2,3-trimethyl-3-butyl 3-ethyl-2-pentyl'.2-methyl-2-hexyl, etc. Octyl radicals, e.g.:

n-Octyl' 2-ethyl-hexyl Diisobutyl Capryl Nonyl radicals, e.g.:

Di-isobutyl-carbinyl n-Nonyl Decyl radicals, e.g. n-decyl Dodecylradicals, e.g. lauryl Tetradecyl radicals, e.g. myristyl Hexadecylradicals, e.g. cetyl Octadecyl radicals, e.g. stearyl Alkenyl radicals,e.g.:

Vinyl Propenyl radicals, e.g.:

Allyl Isopropenyl Butenyl radicals, e.g.: n-Butenyl l n-Butenyl-Zn-Butenyl-3 Isobutenyl Pentenyl radicals, e.g.: n-Penteny-l-l'n-Pentenyl-2 n-Pentenyl-3 Hexenyl radicals, e.g.: n-Hexenyl-1nl-Iexenyl-2, etc. 4,4-dimethyl-butenyl-2 3,4-dimethyl-butenyl-l, etc.Heptenyl radicals, e.g. n-heptenyl Octenyl radicals, e.g.:

n-Octenyl Diisobutenyl Nonenyl radicals, e.g. n-nonenyl Decenylradicals, e.g, n-decenyl Dodecenyl radicals, e.g.:

n-Dodecenyl triisobutenyl Alkenyl radicals having the formula C H wheren is an integer from 18 to 38 inclusive,

elg. those derived from paraffin wax, mineral oils, and pctr'olatum. (2)Cycloaliphatic radicals, for example:

Cycloalkyl radicals,-e.g.: I

Cyclopentyl, alkylated-cyclopcntyl, cyclohexyl,

and alkylated-cyclohexyl radicals, c.g.:

Monoand poly-methyl-cyclopentyl radicals Monoand poly-methyl-cyclohexylradicals Monoand poly-ethyl-cyclohexyl radicals Monoandpoly-isopropyl-cyclohcxyl radicals Monoand ply-tert-amyl-cyclohexylradicals n-Octyl-cyclohexyl;radicals Diisobutyl-cyclohexyl (i.e.tert-octy1-cyclohexyl) radicals 'Nonyl-cyclohexyl radicalsDiiso-amyl-cyclohexyl radicals Lauryl-cyclohexyl radicalsCetyl-cyclohexyl radicals Naphthenyl radicals Hydroabietyl radicalsCycloalkenyl radicals, e.g.:

Cyclopentenyl, alkylated-cyclopentenyl, cyclohexenyl, andalkylated-cyclohexenyl radicals,

Monoand poly-methyl-cyclopentenyl radicals Monoandpoly-methyl-cyclohexenyl radicals Monoand poly-ethyl-cyclohexcnyl radicals Monoand poly-isopropyl-cyclohexenyl radicals Monoand poly tertarnyl-cyclohexenyl radicals n-Octyl-cyclohexenyl radicalsDiisobutyl-cyclohcxenyl radicals Nonyl-cyclohexenyl radicalsDiiso-amyl-cyclohexenyl radicals Lauryl-cyclohexenyl radicals Cetyl-cyclohexcnyl radicals Dehydronaphthenyl radicals Abietyl radicals (3)Aryland cycloalkyl-substituted aliphatic radicals,

for example:

(a) Phenyland alkyl-phenyl-substituted alkyl radicals, e.g.:

Benzyl Methyl-benzyl Capryl-benzyl Diisobutyl-benzyl Phenyl-ethylPhenyl-propyl Phenyl-octadecyl (b) Xenyland alkyl-xenyl-substitutedalkyl radicals, e.g.:

Xenyl-methyl Capryl-xenyl-methyl Xenyl-ethyl Diisobutyl-xenyl-methyl (c)'Napthyland alkyl-naphthyl-substituted alkyl radicals, e.g.:

Naphthyl-methyl Tert-arnyl-naphthyl-methyl Naphthyl-ethylCetyl-naphthyl-ethyl (d) Cyclohexyland alkyl-cycloheXyl-substitutedalkyl radicals, e.g.:

Cyclohexyl-ethyl Methyl-cyclohexyl-ethyl 'Ethyl-cycloheXyl-ethylCyclohcxyl-propyl 4 Tert-amyl-cyclohexyl-butyl (4) Oxygen containingaliphatic and cycloaliphatic radicals, for example:

(a) Oxygen-containing aliphatic radicals, e.g.:

Alkoxy-substitutcd alkyl radicals, e.g.: Propoxy-ethyl radicals, e.g.:

n-Propoxy-ethyl Iso-propoxy-cthyl Butoxy-ethyl radicals, e.g.

n-Butoxy-ethyl Iso-butoxy-ethyl Tert-butoxy-ethyl Octoxy-ethyl radicals,e.g.:

n-Octoxy-ethyl Diisobutoxy-ethyl Di-butoxy-propyl radicals, e.g.:

2,3-di-n-butoxy-propyl 3,3-di-iso-butoxy-propyl Di-octoxy-propylradicals, e.g.:

3,3-di-n-octoxy-propyl 2,3-bis-(diis0butoxy)propylCycloalkoxy-substituted alkyl radicals, c.g.:

Cyclohexoxy-methyl Cyclohexoxy-ethyl radicals, e.g.:Beta-cyclohexoxy-ethyl Alpha-cyclohexoxy-ethyl Cyclohexoxy-butylradicals, e.g.: 2-(cyc1ohex0xy)-butyl 2,3-di-cyclohexoxy-butylMethyl-cyclohexoxy-propyl radicals, e.g.:

2- (o-methyl-cyclohexoxy) -propyl 2- p-methyl-cyclohexoxy) -pr0pylButyl-cyclohexoxy-ethyl radicals, e.g.:

Betap-tert-butyl-cyclohexoxy) -ethyl Alpha-(o-scc-butyl-cyclohexoxy)-ethyl Cyclopentoxy-ethyl radicals, e.g.:

Alpha-cyclopentoxy-ethyl Bct-a-cyclopentoxy-ethylPropyl-cyclopentoxy-rnethyl radicals, e.g.:

-Iso-propyl-cyclopentoxy-methyl radicals n-Propyl-cyclopentoxy-methylradicals Alkenoxy-substituted alkyl radicals, e.g.: Propenoxy-ethylradicals, e.g.:

Allyloxy-ethyl Iso-propenoxy-ethyl Octenoxy-ethyl radicals, e.g.diisobutenoxyethyl Di-octenoxy-propyl radicals, e.g. 2,3-bis-(diisobutenoxy)-propyl Aroxy substituted alkyl radicals, for example,phenoxy and alkyl-phenoxy-substituted alkyl radicals, e.g.:

Phenoxy-methyl Phenoxy-ethyl Cetyl-phenoxy-ethyl Phenoxy-phenethylCapryl-phenoxy-phenethyl b) Oxygen-containing cycloaliphatic radicals,e.g.:

Alk0xy-, alkenoxy-, and aroxy-substituted cycloalkyl radicals, e.g.:

Alkoxy substituted cyclopentyl radicals,

Monoand poly-ethoxy-cyclopentyl Octoxy-cyclopentyl radicals, e.g.dissobutoxy-cyclopentyl Alkoxy-substituted cyclohexyl radicals, e.g.:

Monoand poly-methoxy-cyclohexyl Octoxy-cyclohcxyl radicals, e.g.diisobutoxy-cyclohexyl Alkenoxy-substituted cyclopentyl radicals,

Propenoxy-cyclopentyl radicals, e.g.:

Allyloxy-cyclopentyl Methyl-polychloro-phenyl radicals, e.g.:

Methyl-dichloro-phenyl radicals Methyl-trichloro-phenyl radicalsEthyl-monochloro-anthracyl radicals, e.g,:

Ethyl monochloro alpha anthracyl radicals Triethyl monochlorobeta-anthracyl radicals Ethyl-polychloro-anthracy1 radicals, e.g.:

Ethyl-dichloro-alpha-anthracyl radicals Diethyl-trichloro-beta anthracylradicals Alkyl-nitro-aryl radicals, e.g.:

Methyl-nitro-phenyl radicals Dimethyl-nitro-phenyl radicalsEthyl-dinitro-phenyl radicals Butyl-nitro-naphthyl radicals, e.g.:

Tert-butyl-nitro-naphthyl radicals Sec butyl dinitro-naphthyl radicalsPropyl-nitro-phenanthryl radicals, e.g.: Isopropyl dinitro phenanthrylradicals Di-n-propyl-dinitro phenanthryl radicals Of those set outabove, the preferred secondary amino groups are those having a molecularweight of less than 300.

For clarity, we have illustrated below the formulae of the compoundswhen, in Formula I, X is oxygen, B is diethylamino, A is a quaternaryammonium radical (pyridinium) and M is an anionic charge, and when A andM together are a monovalent carbon-oxygen bond.

A preferred group of compounds within the present invention is the grouphaving the formula wherein X is oxygen or sulfur; B is a secondary aminogroup, said secondary amino group containing in addition to its singlenitrogen atom solely the elements carbon and hydrogen; A is hydrogen,hydroxyl, (1ower)alkanoyloxy, benzoyloxy, a quaternary ammonium radicalor, when taken together with M, a monovalent carbon-oxygen bond; and Mis hydrogen, a pharmaceutically acceptable nontoxic cation, an anioniccharge when A is a quarternary ammonium radical or, when taken togetherwith A, a monovalent carbon-oxygen bond.

Another preferred group of compounds within the present invention is thegroup having the formula wherein X is oxygen or sulphur; B representsdi(lower)- alkylamino wherein the alkyl group may be alike or different,piperidino, methyl-piperidino, dimethylpiperidino, pyrrolidino,rnethylpyrrolidino, dimethylpyrrolidino, morpholino, methylrnorpholino,dimethylmorpholino, N'- (lower)alkylpiperazino, N (lower)alkylmethylpiperazino, N'-(lower)alkyl-dimethylpiperazino,trimethyleneimino, hexamethyleneimino or a radical of the formulaAr-(OH,),,-N- 1'1 wherein n is zero, one, two or three, R is(lower)alkyl and Ar is a radical of the formula I I N wherein R and Rare each hydrogen, fluoro, chloro, bromo, (lower)alkyl or (lower)alkoxy;A is hydrogen, hydroxyl, (lower) alkanoyloxy, benzoyloxy, a quaternaryammonium radical or, when taken together with M, a monovalentcarbon-oxygen bond; and M is hydrogen, a pharmaceutically acceptablenontoxic cation, an anionic charge when A is a quaternary ammoniumradical or, when taken together with A, a monovalent carbon-oxygen bond.

The most preferred embodiments of the present invention are the freeacids and salts thereof of which the free acids have the formulae Theproducts of the present invention wherein X of Formula I is sulfur areprepared by the reaction of a compound of the formula wherein A and Mare described above (preferably in the form of a neutral salt such asthe sodium salt or the triethylamine salt, i.e. when A is hydrogen,hydroxy, (lower)alkanoyloxy or benzoyloxy) with an acid having theformula (in which B has the meaning set forth above) or with itsfunctional equivalent as an acylating agent for a pri mary amino group.The preferred reagent is the mixed anhydride prepared by reacting suchan acid with isovaleryl chloride (or pivaloyl chloride) in the presenceof a tertiary amine such as triethylamine as an acceptor of hydrogenchloride. Such equivalents include the corresponding carboxylicchlorides, bromides, acid anhydrides, including mixed anhydrides andparticularly the mixed anhydrides prepared from stronger acids such asthe lower aliphatic monoesters of carbonic acid, of alkyl and arylsulfonic acids and of more hindered acids such as diphenylacetic acidand isovaleric acid. In addition, an acid azide or an active ester orthioester (e.g. with p-nitrophenol, 2,4-dinitrophenol, thiophenol,thioacetic acid) may be used or the free acid itself may be coupled with7-aminocephalosporanic acid after first reacting said free acid withN,N'-dimethylchloroformiminium chloride [cf. Great Britain 1,008,170 andNovak and Weichet, Experientia XXI/ 6, 360 (1965)] or by the use ofenzymes or of an N,N' carbonyldiimidazole or an N,N -carbonylditriazole[cf. South African Patent Specification 63/2684] of a carbodiimidereagent [especially N,N'- dicyclohexylcarbodiimide,N,N-diisopropylcarbodiimide orN-cyclohexyl-N'-(2-morpholinoethyl)carbodiimide; cf. Sheehan and Hess,J. Amer. Chem. Soc. 77, 1067, (1955)], or of alkynylamine reagent [cf.R. Buijle and H. G. Viehe, Angew. Chem. International Edition 3, 582(1964)], or of a ketenimine reagent [cf. C. L. Stevens and M. E. Monk,J. Amer. Chem. Soc. 80, 4065 (1958)] or of an isoxazolium salt reagent[cf. R. B. Woodword, R. A. Olofson and H. Mayer, J. Amer. Chem. Soc. 83,1010 (1961)]. Another equivalent of the acid chloride is a corresopndingazolide, i.e. an amide of the corresponding acid whose amide nitrogen isa member of a quasiaromatic five-membered ring containing at least twonitrogen atoms, i.e. imidazole, pyrazole, the triazoles, benzimidazole,benzotriazole and their substituted derivatives. As. an example of thegeneral method for the preparation of an azolide,N,N'-carbonyldiirnidazole is reacted with a carboxylic acid in equimolarproportions at room temperture in tetrahydrofuran, chloroform,dimethylforamide or a similar inert solvent to form the carboxylic acidimidazolide in practically quantitative yield with liberation of carbondioxide and one mole of imidazole. Dicarboxylic acids yielddiimidazolides. The by-product, imidazole, precipitates and may beseparated and the imidazolide isolated, but this is not essential. Themethods for carrying out these reactions to produce a cephalosporin andthe methods used to isolate the cephalosporin soproduced are well-knownin the art (cf. US. Patents Nos. 3,079,314, 3,117,126 and 3,129,224 andBritish Patents Nos. 932,644, 957,570 and 959,054).

The compounds of Formula VI used in the present invention include7-aminocephalosporanic acid and derivatives of 7-aminocephalosporanicacid. 7-amin0cephalosporanic acid is prepared by hydrolysis ofcephalosporin C and has theformula l coon 1 I C-CHzOL CH3 Acidhydrolysis of cephalosporin C to produce 7- aminocephalosporanic acidresults in the coproduction of the lactone,3-hydroxymethyl-7-aminodecephalosporanic acid lactone, formed by thefurther hydrolysis of the acetoxy group and subsequent internalesterification. The lactone has the formula Enzymatic hydrolysis of theacetoxy group of 7- aminocephalosporanic acid results in the formationof 3- hydroxymethyl 7 aminodecephalosporanic acid having the formula andhas been given the name 3-pyridiniummethyl-7-aminodecephalosporanic acidinner salt.

The foregoing nuclei and the preparation thereof are known in the artand are described for example in US. Patent No. 3,117,126 and BritishPatents Nos. 932,644, 957,570 and 959,054.

3-methyl-7-aminodecephalosporanic acid having the formula is produced bycatalytic reduction of cephalosporin C followed by hydrolytic removal ofthe S-aminoadipoyl side chain as described in US Patent No. 3,129,224.

There is thus provided by the present invention a method for preparingantibiotic compounds having the general formula wherein X is oxygen orsulfur; B is a secondary amino wherein R taken alone, is OH, C -Cacyloxy or tertiary-amino, R is OH when R is OH;

R is OH when R isC -C acyloxy; R is when R is tertiary-amino;

' I R and R when taken together are O;

which comprises acylating a compound having the bicyclic ring structureof cephalosporin C and having a general formula represented by one ofwhere R is OH or a C -C acyloxy group and s H N-CH-(JH o0,

0=c--N C-CHz-Am 0 1-0 II 0 wherein Am is a tertiary-amino group; with anacylating agent having at least one constituent radical of the generalformula it I? BC-SCHa-C- in which B and X have the meaning set forthabove.

There is further provided by the present invention a method according toclaim 15 for preparing antibiotic compounds having the general formulawherein X is oxygen or sulfur; B is a secondary amino group;

wherein R taken alone, is -OH, C -C acyloxy or tertiary-amino, R is -OHwhen R is OH;

R is OH when R is C -C acyloxy; R is 0 when R is tertiary-amino;

R and R when taken together are O which comprises acylating a compoundhaving the bicyclic ring structure of cephalosporin C and having ageneral formula represented by one of wherein R is OH or a C -C acyloxygroup and wherein Am is a tertiary-amino group; with an acylating agenthaving at least one constituent radical of the general formula X 0 B-('i-SCHz( J wherein B and X have the meaning set forth above; and

(a) Heating the product with acidified water to form the correspondingacylated derivative of the nuclei of cephalosporin C compounds, or

(b) Refiuxing the product in solution with an excess of a tertiary aminecorresponding to Am to form the corresponding acylated derivative of thenuclei of cephalosporin C compounds, or (c) Treating the product withcitrus acetylesterase in a buifered aqueous medium to form thecorresponding N-acylated derivative of the nuclei ofdesacetyldecephalosporin C compounds.

There is also provided by the present invention a method for preparingnontoxic derivatives of the compounds produced by the methods set outabove which comprises combining said products with pharmaceuticallyacceptable cations, anions, alcohols, ammonia or amines.

The products of the present invention wherein X of Formula I is oxygenare prepared in similar fashion by the use of an acid of the formula 0B-fi-S-CHrCOOH (in which E has the meaning set forth above) or itsfunctional equivalent as an acylating agent for a primary amino group.This is not the preferred method, however, as the acids of the formulaare not quite as easily prepared when X is oxygen as they are when X issulfur.

A very effective and most unexpected method for producing the compoundsof Formula I wherein X is oxygen is the process provided by the presentinvention of reaction of a compound of Formula IV directly with an acidof the formula S I B-(i-S-CHzCO OH speed the reaction within reasonablelimits, e.g. about O50 C. The iodide/sodium iodide solution is,preferably but not necessarily, added gradually to the aqueous 1B-OS-CH3GOOH wherein B is a secondary amino group and X is oxygen orsulfur are prepared by the methods reported in the literature andexemplified below, i.e. from the appropriate secondary amine (B-H) asfollows:

KOH 1. ClCHzCOONa B--H+ C8; B-C-SK ---9 KOH ll 1. ClOHzCOONa. B-H+ COSB-CSK 1 B--S-CHzCOOH Procedure No. 1

To a solution of diethylamine (36.57 g.; 0.5 mole) in 300 ml. absoluteethanol there was added 32.75 g. (0.5 mole) of 85.4% aqueous potassiumhydroxide. When the solution had cooled to room temperature there wasadded to it 38.07 g. (0.5 mole) carbon disulfide. After stirring for 2.5hours the solvent was removed by distillation in vacuo to leave theproduct, potassium N,N-diethyldithiocarbamate as a yellow oil whichcrystallized on cooling and was used directly in the next reaction bydissolving it in about 150 ml. water and adding thereto with stirring58.3 g. soduim chloroacetate. The dark green mixture thus produced washeated in a steam bath for one hour. The pH was adjusted to 2 withhydrochloric acid. The product, carboxymethylN,N-diethyldithiocarbamate, separated as an oil which crystallized uponthe addition of more water and cooling as tan crystals where werecollected, recrystallized from hot water and found to weigh 51.5 g. andto melt at 94-96" C. K. A. Jensen, J. Prakt. Chem., 159, 189-192 (1941)reported M.P. 89 C.

Analysis.-Calcd for C7H13NS202: C, 40.5; H, 6.32. Found: C, 40.98;40.82; H, 6.38; 6.40.

Potassium hydroxide (6.55 g., 0.1 mole) was dissolved in 125 ml.absolute ethanol and cooled to 20 C. Carbon disulfide (7.6 g., 0.1 mole)and piperidine (8.5 g., 0.1

mole) were added and the solution was cooled and stirred for thirtyminutes. The solvent was removed by distillation in vacuo to leave theproduct potassium N,N-penta- 14 methylenedithiocarbamate, as a faintlyyellow, crystalline solid, 20.4 g., M.P. 228 C.

Potassium N,N-pentamthylenedithiocarbamate (9.95 g.,' 0.05 mole) andsodium chloroacetate (5.8 g., 0.05 mole) were combined in 50 ml. waterand heated at 30- 35 C. for 1.3 hours. The solution was filtered andcooled. Acidification to pH 2 with hydrochloric acid precipitatedcrystalline S-carboxyrnethyl N,N-pentamethylenedithiocarbamate(which isalso named l-piperidinecarbodithioic acid, carboxymethyl ester), whichwas collected by filtration and found to weigh 8.68 g., M.P. 148149 C.

G. Nachmais, Ann. Chi'm. (Paris), 7, 584-631 (1952); Chem. Abstr., 45,7963 and 48, 597 reported M.P. 143 C.

To a solution of morpholine (26.1 g., 0.3 mole) in ml. water there wasslowly added 22.8 g. (0.3 mole) carbon disulfide and 11.7 g. (0.3 mole)potassium hydroxide. Soon the solution was homogeneous and then 34.2 g.(0.03 mole) sodium chloroacetate was added and the mixture was heated onthe steam-bath for thirty minutes. It was necessary to add a fewmilliliters of 10% sodium hydroxide to keep the pH above 8. The mixturewas filtered and acidified to pH 2 with dilute phosphoric acid toprecipitate the product, herein called S-carboxymethylmorpholino-dithiocarb-amate having the structure given above and alsonamed 4-morpholinecarbodithioic acid, carboxymethyl ester, which wascollected, recrystallized from hot isopropyl alcohol and found to weigh26 g., M.P. 169170 C.

G. Nachmais, ibid, reported M.P. 162 C.

Procedure N 0 4 0113 ll: ClCHaCOONa 2. HCI

s H @om-n-o-s-omo 0 0H Procedure N 0. 5

1. 01015120 0 0Na 2. H01

5 I @n-d-s-omoo on Potassium hydroxide (6.55 g.) was dissolved in 100ml. water and cooled in ice. The icebath was removed and carbondisulfide (6.03 ml.) and N-methylaniline (10.85 ml.) were added. Themixture was stirred for four hours; most of the oil disappeared. Sodiumchloroacetate (10.0 g.) was added and the pH was lowered to about 7. Thesolution was stirred for 40 minutes and then acidified to pH 2 with HClto precipitate the product, carboxymethylN-phenyl-N-methyldithiocarbamate, as a crystalline solid which wascollected by filtration, 9.4 g., M.P. ZOO-202 C.d.

Analysis.Calcd for C H NO S C, 49.76; H, 4.60; S, 26.58. Found: C,50.16; H, 4.77; S, 27.05.

Holmberg, J. Prakt. Chem. 2, 82, 446; Beilstein, 12, I, 252 reportedM.P. 197198 C.

1. C1-CHzCOONa Pyrrolidine (10.64 g., 0.15 mole) was dissolved in asolution of 8.25 g. KOH in 100 ml. water and cooled to C. Carbondisulfide (11.4 g., 0.15 mole) was added in 2 ml. portions whilestirring in ice; when the additions were complete the pH was slightlyalkaline, Sodium chloroacetate (17.5 g., 0.15 mole) was added and thesolution was warmed on a hot plate. Stirring was continued for 40minutes. The solution was acidified with hydrochloric acid and theprecipitated product, S-carboxymethyl N,N-tetramethylenedithiocarbamate(also named 1-pyrrolidinecarbodithioic acid, carboxymethyl ester), wascollected by filtration and recrystallized from methanol to yield 21.5g., M.P. l62l63 C.

Analysis.Calcd for C H Ns O z C, 41.0; H, 5.30; N, 6.84. Found: C,41.29; H, 5.55; N, 6.80.

Afanaseva, Chem. Abstr. 54, 20997i 141-143 C.

reported PROCEDURE NO. 7

Diethylamine (14.6 g., 0.2 mole) was dissolved in 150 ml. diethyl etherand carbonyl sulfide was bubbled into the cooled solution until 6.0 g.(0.1 mole) had been added. The solution was stoppered and storedovernight. The solvent was removed at 33 C. to leave as the residue13.67 g. of diethylammonium N,N-diethylthiocarbamate as an oil whichcrystallized on cooling and was then dissolved in 75 ml. water. Sodiumchloroacetate (7.74 g., 0.066 mole) was added and the solution wasstirred at room temperature for 3 hours, heated at 50-55" C. for 50minutes and then stored overnight at room temperature. The solution wasacidified with HCl and extracted with ether. The ethereal extract waswashed twice with water and dried over MgSO Removal of the solvent bydistillation left as the residue 6.5 g. S-carboxymethyl N,N-diethylthiocar bamate as an oil which crystallized on standing in iceand was heated slowly to 50 C. in vacuo (water pump) and then allowed tostand. Melting point 36-38 C.

Analysis.Calcd for C7H13NO3SZ C, 43.96; H, 6.85; N, 7.32. Found: C,44.00; H, 7.01; N, 7.36.

PROCEDURE NO. 8

1. ClCHgG O ONa 2. 1101 SCH;COOH

A solution of 13.1 g. (0.2 mole) potassium hydroxide in 100 ml. waterwas cooled to 15 and l-methylpiperazine (20. 0g., 0.2 mole) was added.Carbon disulfide (12.0 ml., 0.2 mole) was then added in 2 ml. portionswhile maintaining the temperature at about 10 C., taking minutes for theadditions. The pH was then lowered to 9 with HCl. Sodium chloroacetate(23.2 g., 0.2 mole) was added and the mixture was stirred overnight andthen filtered to remove a small amount of a precipitate. The filtratewas evaporated at 38 C. to leave the product, S- carboxymethyl1-methylpiperazino-dithiocarbamate (also called1-methyl-4-piperazinecarbodithioic acid, carboxymethyl ester), as asolid residue which was recrystallized from methanolether. On standingin water at pH 6 the produce crystallized and was found to have an NMRspectrum consistent with the assigned structure.

In the process for the preparation of the compounds of Formulae (I) and(VII) above, the compounds are sometimes in aqueous solution in the formof their sodium or potassium salt. These compounds in the aqueous phasecan then be converted to the free acid, preferably in the cold under alayer of ether by the addition of dilute mineral acid, e.g. 5 N H 50 topH 2. The free acid can then be extracted into a water-immiscible,neutral organic solvent such as ether, the extract washed with waterquickly in the cold, if desired, and dried, as with anhydrous Na 'SO andthe free acid recovered from the ethereal solution. The product in theethereal extract in its free acid form can then be converted to anydesired metal or amine salt, particularly the pharmaceuticallyacceptable nontoxic amine salts described above, by treatment with theappropriate base, e.g. a free amine such as procaine base or a solutionof potassium Z-ethylhexanoate in dry n-butanol. These salts are usuallyinsoluble in solvents such as ether and can be recovered in pure form bysimple filtration.

The following examples will serve to illustrate this invention withoutlimiting it thereto. All temperatures are given in degrees centigrade.

In the structural formulae given below -ACA represents the moiety havingthe formula To a solution of 1. 8 g. (0.001 mole) of S-carboxymethylN,N-dimethyldithio-carbamate (Eastman Kodak Co.) and 1.0 g. (0.001 mole)triethylamine in 50 ml. tetrahydrofuran (THF) there was added at 0 C.1.2 g. (0.001 mole) of isovaleryl chloride. A white precipitate formedwhich dissolved upon the addition of 2.8 g. (0.001 mole)7-aminocepholosporanic acid (7-AOA) as its triethylammonium saltdissolved in water. The tetrahydrofuran was removed by evaporation underreduced pressure at 35 C. The remaining aqueous mixture was diluted withwater and acidified to pH 2 with dilute phospheric acid and extractedinto ethy-lacetate which was cedure No. 3) dissolvediin 100 ml.tetrahydrofuran there was added 1.6 g. (0.0158 mole) triethylamine andthen, at C., 1.9 g. (0.0158 mole) isovaleryl chloride (D.P.I.). Themixture was stirred for15 minutes and there was then added a solution of4.3 g. (0.015 8 mole) 7-aminocephalosporanic. acid dissolved in waterbythe addition of su fiicient triethylamine to dissolve it completely. Theresulting clear solution was stirred for 30 minutes and thetriethylamine was evaporated off at 30 C. under reduced pressure. Theaqueous phase was lowered to pH 2 with dilute phosphoric acid and theproduct in its acid form wasthen extracted into ethyl acetate. The ethylacetate extract was washed with water, dried over MgSO .and filtered. Tothe filtrate there was then added sodium 2- ethylhexanoate whichprecipitated the product of the formula given above;'it was collected,dissolved in a minimum amount of Water, reprecipitated by the additionof acetone, collected, recrystallized three times from wet n-butanol andfound to weight 4 g. Analysis.Calcd for C H NaN O S C, 41.00; H,1.03;"N, 8.45.'Found: C, 41.03; H, 4.03; N, 8.22.

This product exhibited Minimum Inhibitory Concentrations (M.I.C.s) ofabout 0.25 mcg./ml. versus S. aureus Smith, of about 1.6 mcg./ml. versusthe benzylpenicillinresistant Staph. aureus BX-1633-2 of about 1.6meg/ml. versus the benzylpenicillin-resistant Staph. aureus 52-75, ofabout 0.25 meg/m1. versus D. pneumoniae and of about 0.25 mcg./ ml.versus Str. pyrogenes Digonnet 7.

Example 5 To 2.4 g. (0.01 mole) of S-carboxymethyl N-phenyl-N-methyldithiocarbamate (prepared according to Procedure No. 5) in 100ml. tetrahydrofuran there was added 1.0 g. (0.01 mole) triethylamine.The solution was cooled to 0 C. in an ice-bath and 1.2 g. (0.01 mole)pivaloyl chloride (trimethylacetyl chloride) was added. The mixture wasstirred for ten minutes and there was then added a solution in 100 ml.water of 2.7 g. (0.01 mole) 7-aminocephalosporanic acid and 10 ml.triethylamine. The solution was stirred for 30 minutes and then theorganic solvent was evaporated under reduced pressure to leave anaqueous solution of the triethylamine salt of the product which wasconverted to its acid form by diluting with 20% phosphoric acid andextraction into ethyl acetate. The ethyl acetate extract was dried overanhydrous ,MgSO Addition thereto of sodium 2-ethylhexanoate in dryn-butanol precipitated 3 g. of the product of the formula given abovewhich was dissolved in wet n-butanol and azeotroped at 40 C. to give acrystalline solid with some oil present. The solid was collected,dissolved in 100 ml. wet butanol and evaporated under reduced pressureto the point where an oil precipitated. Diatomaceous earth (Celite) wasadded and the mixture was filtered. Azeotroping of the filtrate wascontinued to precipitate the product as crystalline rosettes, 200 mgm.

Analysis.--Calcd for C H NaN O S C, 46.42; H,

3.90; N, 8.12. Found: C, 46.60; H, 4.12; N, 7.85.

This product exhibited Minimum Inhibitory Concentrations (M.I.C.s) ofabout 0.125 mcg./ml. versus S.

aureus Smith, of about 0.4 mcg./ml. versus thebenzylpenicillin-resistant Staph. aureus BX-1633-2, of about 0.4 meg/ml.versus the benzylpenicillin-resistant Staph. aureus 52-75, of about0.06-0.125 meg/ml. versus D. pneumoniae and of about 0.062 meg/ml.versus Str. pyogenes Digonnet 7.

Example 6 S O H H N-o-s oH c AoANa 'S- -"carboxymethyl N,N-'tetramethylene-dithiocarbamate (p'repared'according to Procedure No. 6and also named l-pyrrolidine-carbodithioic acid, carboxymethyl ester)=Twas used in the process of the above examples to produce 'theproductof theformula given above in 42% yield; Its decomposition pointafter recrystallization from water-acetone was 160 C.

Analysis.Calc.d for. C N NaN O S -3H O: C, 39.45; H, 4.68; N, 8.12.Found: C, 39.59; H, 4.45; N, 7.50." i v N methyl Nbenzyldithiocarbamylacetic acid (2.5 g'., 0.01 mole, prepared accordingto Procedure No. 4 and also'namedS carboxymethyl N methyl N-benzyldithiocarbarnate) was dissolved in 100 ml. tetrahy drofurantat 5-C..and 1. g. .triethylamine was added. The solution was stirred for tenminutes in an ice-bath and 1.2 g. (0.01 mole) isovaleryl chloride(Eastman Kodak Co.) was added. A white precipitate formed immediately.An aqueous solution of 2.7 g. (0.01 mole) 7-aminocephalosporanic acidsolubilized by the addition of triethylamine was added all at once toproduce a clear solution which was stirred 15 minutes. Thetetrahydrofuran was removed by evaporation, 50 ml. water Was added andthe pH was lowered to 2 with dilute phosphoric acid to convert theproduct to the acid form which was then extracted into ethyl acetate.The sepa rated ethyl acetate was washed with water, dried over anhydrousMgSO and treated with sodium 2-ethylhexanoate to precipitate 560 mgm. ofthe product having the formula given above.

Analysis.-Calcd for C H NaN O S C, 47.45; H, 4.17; N, 7.90. Found: C,47.93; H, 4.47; N, 7.82.

This product exhibited Minimum Inhibitory Concentrations (M.I.C.s) ofabout 0.125-1.0 mcg./ml. versus S. aureus Smith, of about 0.4 mcg./m1.versus the benzylpenicillin-resistant Staph. aureus BXl633-2, of about0.4 mcg./ml. versus the benzylpenicillin-resistant Staph. aureus 52-75,and of about 0.5 meg/ml. versus Str. pyogenes Digonnet 7.

aminocephalosporanic acid (6.82 g., 0.025 mole) were combined in 150 ml.water and adjusted to pH 7 with NaOH. The solution was cooled to 4% C.and 25 ml.

cold 1 N potassium iodide-iodine solution (i.e. prepared by'dissolving166.01 g. potassium iodide and 253.81 g. iodine q.s. to one liter inwater) was added. The pH was kept at about -7 by adding sodiumhydroxide. Stirring was continued for about 20 minutes after the lastaddition of KII solution. The reaction mixture was then acidified with HPO and shaken with ethyl acetate; the whole mixture was filtered toremove unreacted 7- aminocephalosporanic acid so that the phases couldbe separated. The separated ethyl acetate phase containing the free acidform of the product was washed with water and the solvent was removed at35 C. to precipitate 4.3 g. of crystalline product as the free acid. Thematerial was partially dissolved in hot ethyl acetate, filtered and thediethyl ether was added. to the filtrate. Storing overnight in the coldprecipitated crystals of the product (as the free "acid monohydrate)which were collected, .washedwith a little ether, dried at 56 C. invacuo over P 0 425 mgm., M.P. 96 C. An analytical sample wasrecrystallized from acetone-water and dried in vacuo over PAnalysis.-Ca1cd for c15H19N OqS /2H2OI C, H, 4.71; N, 9.82; S, 14.99.Found: C, 41.74; H, 4.95; N, 9.51; S, 15.57; H O, 2.42.

This product exhibited Minimum Inhibitory Concentrations (M.I.C.s) ofabout 0.5 mcg./ml. versus S. aureus Smith, of about 0.8 mcg./ml. versusthe benzylpenicillin-resistant Staph. aureus BX-l633-2, of about 0.8mcg./rnl. versus the benzylpenicillin-resistant Staph. aureus 52-75, ofabout 0.5 mcg./ml. versus D. pneumom'ae, of about 0.25 meg/ml. -versusStr. pyogenes Digonnet 7 and of about 3.1 mcg./ml. versus S.enteritidis.

Example 9a CHQCHQ O O CH CH;

7-arninocephalosporanic acid (80% pure, 1.36 g., 0.005 mole) and3-carboxymethyl N,N-diethyl-dithiocarbamate (1.24 g., 0.006 mole,prepared by Procedure No. 1) were dissolved in 100 ml. 2 M pH 7phosphate buffer maintained at pH 7 by the addition of sodium hydroxide.A 1 N solution of 1 in 1 N NaI (10 ml.) was added over a 20 minuteperiod with both solutions held at 4 C. After adjusting the pH to 7 with10% NaOH the solution was stirred for two hours at room temperature. Thereaction mixture was filtered to remove a small amount of solid and thefiltrate was extracted with ether. The aqueous phase was acidified with40% H PO and the free acid form of the product was extracted into ethylacetate. The ethyl acetate extract was washed with water and the solventwas removed to leave the product as an oil which was converted by use ofsodium 2-ethylhexanoate to the monohydnate of the product of the formulagiven above. Recrystallization from acetone-dimethyltormamide gave 160mgm., M.P. 152-155 C. with decomposition.

This product exhibited Minimum Inhibitory Concentrations (M.I.C.s) ofabout 0.25-0.31 meg/ml. versus S. aureus Smith, of about 0.8 mcg./ ml.versus the benzylpenicillin-resistant Staph. aareus BX-1633-2, of about0.8 meg/ml. versus the benzylpenicillin-resistant Staph. aureus 52-75,of about 0.31-015 meg/ml. versus D. pneumonia and of about 0.16-0.25meg/ml. versus Str. pyogenes Digonnet 7.

This product is exceptionally well absorbed upon oral administration.

Example 9b CHaCH: O H

N-ii-s-oHl-o-AOA-Na CHaCHg (from 7-aminocephalosporanic acid (8.7 g.,0.032 mole) and S-carboxymethyl N,N-diethyldithiocarbamate (7.25 g.,0.035 mole) were combined in 200 ml. pH 7 phosphate buffer (0.2 M),cooled to 8 and adjusted to pH 7 with NaOH; to this mixture there wasadded 98 ml. of 1 N Kl-I solution. The solution was stirred until the pHremained constant; some I was unreacted. The solution was acidified andextracted with ethyl acetate. The organic layer was washed with waterand the solvent evaporated to leave the free acid form of the product asan oil. Acetone was added and then sodium 2-ethylhexanoate toprecipitate 5.2 g. of the product of the formula given above.

This material was recrystallized successively from acetone-water andbutanol-water twice, dried over P 0 and submitted for analysis.

CHaCHz S /N- SC H20 0 OH CHaCHg 22 Analysis.Calcd for C H NaN O OS -H O:C, 41.64; H, 4.93; N, 8.57. Found: C, 41.91; H, 5.21; N, 8.60; H O,4.64.

Example CHaCHa CHQCHB 0 from To a cooled solution ofN,N-diethylcarbamoylacetic acid (3.2 g., 0.0167 mole, prepared accordingto Procedure No. 7) and 1.77 g. (0.0175 mole) triethylamine in ml.tetrahydrofuran there was added 2.12 g. (0.0175 mole) isovalerylchloride. Stirring was continued for 20 minutes. There was then added acooled solution of 5 ml. triethylamine and 4.82 g. (0.0167 mole) 7-aminocephalosporanic acid in 50 ml. water and stirring was continued for25 minutes. The solution was diluted with cold water, acidified with HPO and extracted with ethyl acetate. The ethyl acetate extract waswashed two times with water, filtered and the solvent evaporated toleave the free acid of the product as an oil which was then dissolved inacetone to which was added a solution of sodium 2-ethylhexanoate inacetone. The product of the formula above precipitated in crystallineform and was collected and recrystallized from water-acetone to yield2.5 g.

CHgCHz Example 10 7-aminocephalosporanic acid (6.44 g., 0.024 mole) andS-carboxyrnethyl N,N pentamethylenedithiocanbarnate (4.38 g., 0.02 mole,prepared according to Procedure No. 2 and also named1-piperidine-carbodithioic acid, carboxymethyl ester) were almostcompletely dissolved in ml. pH 7 0.2 molar phosphate buffer at 0 C.There was then added over 20 minutes 62 ml. 1 N 1;; in 1 N K1 solution.The solution was stirred for an additional hour while warming towardroom temperature. The solution was filtered. and extracted with ethylacetate. The aqueous phase was separated, acidified with H PO and theproduct in its acid form was extracted into ethyl acetate. The ethylacetate was separated and washed with water and the ethyl acetate wasremoved at 33 C. to leave the product as an oil which was diluted withacetone and filtered. The addition of sodium 2- ethylhexanoateprecipitated the product as its sodium salt (having the formula givenabove) as fine crystals which became gummy when collected by filtration.The product was dried in vacuo overnight, found to weigh 3.7 g.,recrystallized from aqueous n-butanol and again from a mixture of onepart water and one part dioxane to which three parts of acetone wereadded.

Analysis.Ca-lcd for C H NaNgO s- C, 45.09; H, 4.63; N, 8.76. Found: C,45.17; H, 4.94; N, 8.49.

This product exhibited Minimum Inhibitory Concentrations (M.I.C.s) ofabout 0.25 meg/ml. versus S. aareus Smith, of about 0.8 mcg./ml. versusthe benzylpenicillin-resistant Staph. aureus BX-1 633-2, of about 0.8meg/ml. versus the benzylpenicillin-resistant Staph. aureus 52-75, ofabout 0.25 meg/ml. versus D. pneumoniae and ofabout 0.25 meg/ml. versusStr. pyogenes Digonnet 7.

This product is exceptionally well absorbed upon oral administration.

7-aminocephalosporanic acid (6.82 g., 0.025 mole) and S-carboxymethylN,N-tetramethylenedithiocarbamate (5.13 g., 0.025 mole preparedaccording to-Procedure No. 6 and also named l-pyrrolidinecarbodithioicacid, carboxymethyl ester) were dissolved in 100 ml. water by adjustingto pH 7 with NaOH; There was then added over 30 minutes 100 ml. of 1 N'1 in 1 N 'Kl solution while adjusting the pH to 7 after each addition.The solution was then stirred for one hour while adding NaOH to keep thepH at 7. It was then acidified with H 1 0, and the product in itsacid'form was extracted into ethyl acetate, which was separated andwashed with water. Evaporation of the solvent left the product as an oilwhich was dissolved in dioxane; addition thereto of sodium 2-ethylhexanoate in acetone precipitated the product as its sodium salthaving the formula given above. The crystals were collected byfiltration, washed with acetone, found to Weigh 4.3 g., recrystallizedfrom butanol-water and then from Water-acetone and dried over PAnalysis.-Calcd for C H NaN O S C, 43.86; H, 4.33; N, 9.03; S, 13.78; HO, none. Found: C, 43.74; H, 4.48; N, 8.93; S, 14.00; H O, none.

This product exhibited Minimum Inhibitory Concentrations (M.I.C.s) ofabout 0.25 meg/ml. versus S. aureus Smith, of about 0.8 meg/ml. versusthe benzyl penicillin-resistant Staph. aureus BX-l633-2, of about 0.8meg/ml. versus the benzylpenicillin resistant Staph. aztreus 52-75, ofabout 0.25 mcg./ml. D. pneumoniae and of about 0.25 meg/ml. versus Str.pyogenes Digonnet 7.

Example 12 7-aminocephalosporanic acid (5.84 g., 0.02 mole) and Scarboxymethyl N methyl N phenyldithiocarbamate (4.82 g., 0.02 moleprepared according to Procedure No. 5) were combined in 225 ml. waterand l N Kl-I solution was added while adjusting to pH 7 as needed withNaOH during the addition. The solution was filtered and acidified with HPO The product in its acid form was extracted into ethyl acetate whichwas separated, washed with water and evaporated to leave the product asan oil which was then taken up in acetone. The addition thereto ofsodium 2-ethylhexanoate precipitated the product as its sodium salthaving the formula given above, 2.5 g. The product was dissolved inwater, filtered, decolorized with carbon, diluted with n-butanol andevaporated at 33 C. until an oil began to form. Diatomaceous earth(Celite) was added and the solution was filtered. The filtrate wasevaporated until it became turbid; the addition of acetone thenprecipitated the product as fine crystals, 650 mgm. A portion wasrecrystallized from water-acetone and dried in vacuo over P 0Analysis.-Calcd for C H NaN O S C, 47.90; H, 4.02; N, 8.38; S, 12.79.Found: C, 47.64; H, 4.25; N, 8.22; S, 12.65, 12.45.

This product exhibited Minimum Inhibitory Concentrations (M.I.C.s) ofabout 0.25 meg/ml. versus S. aureus Smith, of about 0.4 meg/ml. versusthe benzylpenicillin-resistant Staph. aureus BX-1633-2, of about 0.4meg/ml. versus the benzylpenicillin-resistant Staph. aureus 52-75, ofabout 0.125 meg/ml. versus D. pneumoniae and of about 0.125 meg/ml.versus Str. pyogenes Digonnet 7.

4 '1 Example. 13

This product is prepared by using in the procedure of Examples 10, 11 or12 the reagent s earboxyme'thyl 1-methylpiperazino-dithiocarbamateprepared according toProcedure No. 8. i

Example 7-aminocephalosporanic acid (6.82 g., 0.025 mole) andS-carboxymethyl morpholinodithiocarbamate (5.13 g., 0.023 mole preparedaccording to Procedure No. 3) were combined in ml. water adjusted to pH7 with NaOH. The mixture was cooled in ice and 25 ml. of 1 N Kl-Isolution was added while keeping the pH at about 7 with NaOH. After theaddition'was complete the solution was stirred for 15 minutes and thenacidified with H PO and extracted with ethyl acetate. The ethyl acetatewas separated and washed with water; removal of the solvent byevaporation left the product in its acid form as an oil which wasdissolved in acetone; the addition thereto of sodium 2-ethylhexanoateprecipitated the product of the formula given above as 4.5 g. crystalswhich were recrystallized from water-acetone. V

This product exhibited Minimum Inhibitory Concentrations (M.I.C.s) ofabout 0.5 mcgJml. versus S. aureus Smith, of about 1.6 meg/ml. versustheben zylpenicillin-resistant Staph. aureus BX-1633-2, of about 1.6meg/ml. versus the benzylpenicillin-resistant Staph. aureus 52-75, ofabout 0.5 meg/ml. versus D.- priedmoniae, of about 0.5 meg/ml. versusStr. pybgenes Digonnet 7 and of about 12.5 meg/ml. versus S.enteritidis.

This product is prepared by mixing 2 g. nicotinamide and 1 g. of theproduct of Example 9 in 10 mlfwater, saturating the solution withnitrogen and storing it at 56 C. for 19 hours.

Example 16 Replacement of the diethylamine in Procedure No. 1 with anequimolar 'weight of the amines having the formula used in theprocedures of Examples 2 nd 9b, respectively, to produce the compoundsof the formula respectively, wherein X is S when Example 245 followedand X is when Example 9b is followed and wherein R and R have themeanings tabulated below:

R R Ethyl Methyl n-Propyl do i-Propyl do n-Butyl do Sec.butyl doTert.-butyl do Iso-butyl do n-Amyl do Iso-amyl do n-Hexyl do Iso-hexyldo 3,3-dimethylbutyl do 2-hexyl do 3-hexyl do Methyl Ethyl n-Propyl doi-Propyl do n-Butyl do Sec.-butyl do Tert.-butyl do Iso-butyl do n-Amyldo Iso-amyl do n-Hexyl do Iso-hexyl do 3,3-dimethylbutyl do Z-hexyl do3-hexy1 do Methyl n-Propyl Ethyl do n-Propyl do i-Propyl do n-Butyl doSec.-butyl do Tert.-butyl do Iso-butyl do n-Amyl do Iso-amyl do n-Hexyldo Iso-hexyl do 3,3-dimethylbutyl do Z-hexyl do S-hexyl do Methyli-Propyl Ethyl do n-Propyl do i-Propyl do n-Butyl do Sec.-butyl doTert.-butyl do Iso-butyl do n-Amyl do Iso-arnyl do n-Hexyl do Iso-hexyldo 3,3-dimethylbutyl do 2-hexyl do 3-hexyl do Methyl n-Butyl Ethyl don-Propyl do i-Propyl do n-Butyl do Sec.-butyl do Tert.-butyl doIso-butyl do n-Amyl do Iso-arnyl do n-Hexyl do Iso-hexyl do3,3-dimethylbutyl do R R 2-hexyl do S-hexyl do Methyl iso-Butyl Ethyl don-Propyl do i-Propyl do n-Butyl do Sec.-butyl do Tert.-butyl doIso-butyl do n-Amyl do Iso-amyl do n-Hexyl do Iso-hexyl do3,3-dirnethylbutyl do 2-hexyl do B-hexyl do Methyl sec.-Butyl Ethyl don-Propyl do i-Propyl do n-Butyl do Sec.-butyl do Tert.-butyl doIso-butyl do n-Arnyl do Iso-amyl do n-HeXyl do Iso-hexyl do3,3-dimethylbuty1 do Z-hexyl d0 3-hexy1 do Methyl n-Amyl Ethyl don-Propyl do i-Propyl do n-Butyl do Sec.-butyl do Tert.-butyl doIso-butyl do n-Amyl do Iso-amyl do n-Hexyl do Iso-hexyl do3,3-dimethylbuty1 do 2-hexyl do 3-hexyl do Methyl Iso-amyl Ethyl don-Propyl do i-Propyl do n-Butyl do Sec.-butyl do Tert.-butyl doIso-butyl do n-Amyl do Iso-amyl do n-Hexyl do Iso-hexyl do3,3-dimethylbutyl do Z-hexyl do 3-hexy1 do Methyl n-Hexyl Ethyl don-Propyl do i-Propyl do n-Butyl do Sec.-buty1 do Tert.-butyl doIso-butyl do n-Amyl do 26 R R R R Iso-amyl do 3,3-dimethylbutyl don-Hexyl do 2-heXy1 do Iso-hexyl d0 3-heXyl do 3,3-dirnethylbutyl doMethyl- 3,3-dimethylbutyl Z-hexyl do Ethyl do 3-hexyl do n-Propyl doMethyl Iso-hexyl i-Propyl do Ethyl do n-Butyl do n-Propyl do Sec.-butyldo i-Propyl d0 Tert.-butyl do n-Butyl do Iso-butyl do Sec.-butyl don-Amyl do Tert.-butyl do Iso-amyl do Iso-butyl do n-Hexyl do n-Amyl doIso-hexyl do Iso-arnyl do 3,3-dimethylbutyl do n-Hexyl do 2-hexy1 doIso-hexyl do 3-hexyl do 3,3-dimethylbutyl do Methyl Tert.-buty1 2-hexyld0 Ethyl do 3-hexyl do n-Propyl do Methyl 2-hexyl i-Propyl do Ethyl don-Butyl do n-Propyl do Sec.-butyl do i-Propyl do Tert.-butyl do n-Butyldo Iso-butyl do Sec.-butyl do n-Arnyl do Tert.-butyl do Iso-amyl doIso-butyl do n-Hexyl do n-Amyl d Iso-hexyl do Iso-amyl do3,3-dimethylbutyl do n-Hexyl do Z-hexyl do Iso-hexyl do S-hexyl do3,3-dimethylbutyl do Methyl Neo-pentyl 2-hexy1 do Ethyl do 3-hexyl don-Propyl do Methyl 3-hexy1 i-Propyl do Ethyl do n-Butyl do n-Propyl doSec.-butyl do i-Propyl do Tert.-butyl do n-Butyl do Iso-butyl doSec.-butyl do n-Amyl do Tert.-butyl do Iso-arnyl do Iso-butyl do n-Hexyldo n-Arnyl do Iso-hexyl do Iso-amyl do 3,3-dimethylbutyl do n-Hexyl do2-hexyl do Iso-hexyl do 3-hexyl do Example 17 Replacement of thel-methylpiperalzine in Procedure No. 8 with an equimolar weight ofl-ethylpiperazine, l-n-propylpiperazine, l-isopropylpiperazine, 1-n-butylpiperazine, l-sec.-butylpiperazine, l-tert.-butylpiperazine,l-isobutylpiperazine, l-n-amylpiperazine, l-isoamylpiperazine,l-n-hexylpiperazine,

1-(3',3'-dimethylbutyl) -piperazine,

1-(2'-heXyl)-piperazine,

1- (3 '-hexyl) -piperazine and l-neopentylpiperazine, respectively,

produces the corresponding S-carboxymethyl 1-(lower)-alkylpiperazinodithiocarbamates (also named as the correspondingl-(lower)alkyl-4-piperazine-carbodithioic acid carboxymethylesters)which are used to replace on an equimolar basis the S-carboxymethylN,N-diethyldithiocarbamate used in the procedures of Examples 2 and 9b,respectivelyflo produce the compounds of the formula7-aminocephalosporanic acid (2.7 g., 0.01 mole) and S-carboxymethylN-methyl-N-benzyldithiocarbamate (2.5 g., 0.01 mole, M.P. 102103 C.,prepared by Procedure No. 4) were combined in 80 ml. water and 25 ml. 1n'I -Kl was added to the solution after the material had been dissolvedby adjusting to pH7 with NaOH. While theI -Kl solution was being addedthe pH was maintained at '7 with 10% NaOH. When the addition wascomplete and the solution remained at constant pH, the solution wasextracted with ethyl acetate and then the aqueous phase was acidifiedwith H PO filtered and again extracted with ethyl acetate. The ethylacetate extract was washed with water and dried over MgSO and to it wasadded a solution of sodium 2-ethylhexanoate in acetone to precipitatethe product of the formula given above. After air drying this materialweighed 175 mgm. and was recrystallized from water-n-butanol and driedin vacuo overnight at room temperature and then at 56 C. for two hours.On heating the sample darkened above 153 C. and decomposed at about203-205 C.

While in the foregoing specification various embodiments of thisinvention have been set forth in specific detail and elaborated for thepurpose of illustration, it will be apparent to those skilled in the artthat this invention is susceptible to other embodiments and that many ofthe details can be varied widely without departing from the basicconcept and the spirit and scope of the invention.

We claim:

- 1. A compound having the formula wherein X is oxygen or sulfur;

B represents di(lower)alkylamino wherein the alkyl group may be alike ordifferent, piperidino, methylpiperidino, dimethylpiperidino,pyrrolidino, methylpyrrolidino, dimethylpyrrolidino, morpholino,methylmorpholino, dimethylmorpholino, N'-(lower) albylpiperazino, N(lower)albyl methylpiperazino, N (lower)alkyl dimethylpiperazino,trimethyleneimino, hexamethyleneimino or a radical of the formulawherein n is zero, one, two or three, R- is (lower)alkyl and Ar is aradical of the formula R and R are each hydrogen, fiuoro, chloro, bromo,

(lower)alkyl or (lower) alkoxy;

'A is hydrogen, hydroxyl, (lower)alkanoylox'y, benzoyloxy, a quaternaryammonium radical of the formula wherein each of W and Z is hydrogen ormethyl or, when taken together with M, a monovalent carbonoxygen bond;and

M is hydrogen, a pharmaceutically acceptable nontoxic cation, an anioniccharge when A is a quaternary ammonium radical or, when taken togetherwith A, a monovalent carbon-oxygen bond.

2. A compound of claim 1 having the formula wherein X is oxygenorsulfur, M is a pharmaceutically acceptable, nontoxic cation, n'is'zero, one two or three, R is (lower) alkyl and Ar is a radical of theformula l 1? B it in which R and R are each hydrogen, fluoro, chloro,bromo, (lower)a11cyl or (lower)alkoxy.

4. A compound of claim 1 having the formula X is oxygen or sulfur and Mis a pharmaceutically acceptable, nontoxic cation. 5. A compound ofclaim 1 having the formula X is oxygen or sulfur,

n is one, two, three or four and M is a pharmaceut-ically acceptable,nontoxic cation. 6. A compound of claim 1 having the formula X is oxygenand sulfur and R and R each represent hydrogen or methyl. 7. A compoundof claim 1 having the formula X is oxygen or sulfur, n is one, two,three or four and R and R represent hydrogen or methyl. 8. The acid ofclaim 1 having the formula and its nontoxic, pharmaceutically acceptablesalts.

9. The acid of claim 1 having the formula lit and its nontoxic,pharmaceutically acceptable salts.

11. The acid of claim 1 having the formula 011, (I?

and its nontoxic, pharmaceutically acceptable salts.

12. The acid of claim 1 having the formula and its nontoxic,pharmaceutically acceptable salts.

13. The acid of claim 1 having the formula and its nontoxic,pharmaceutically acceptable salts.

14. The acid of claim 1 having the formula and its nontoxic,pharmaceutically acceptable salts.

15. The acid of claim 1 having the formula CH3 0=C--N 0H10-00H3 0 00011and its nontoxic, pharmaceutically acceptable salts.

16. The acid of claim 1 having the formula and its nontoxic,pharmaceutically acceptable salts.

References Cited UNITED STATES PATENTS NICHOLAS S. RIZZO, PrimaryExaminer.

1. A COMPOUND HAVING THE FORMULA